The overall objective of this project is to evaluate the role of neurotoxicants and aging as stressors that promote pathophysiology of Parkinson's disease (PD) and related neurodegenerative diseases. Our plan for this proposal is to utilize an experimental paradigm that combines new transgenic mouse models with neurotoxicant exposure regimens and aging, with a goal of elucidating specific mechanisms that could explain interactions between pesticides and proteins implicated in parkinsonism. The primary stressors to be tested include environmental agents that have the potential for significant human exposure, making the studies highly relevant to the general public health. Specifically, we will investigate the LRRK2 protein as a common mechanistic link between neurodegenerative conditions with parkinsonism. LRRK2-related PD typically mimics sporadic PD;yet certain mutations in the protein result in remarkable pleomorphism in clinical and pathological phenotype, ranging from no nigral cell loss to frank tau pathology, even within families with the same mutation. Indeed, LRRK2-related syndromes exhibit all the pathological hallmarks associated with PD and related disorders;consequently, this protein has been called the "Rosetta stone" for neurodegenerative disease. LRRK2 mutations are also associated with penetrance that is age-dependent with age of onset ranging from that of typical sporadic PD to as late as the tenth decade. This suggests that full manifestation of the mutation (i.e. disease development) may not occur in some individuals carrying the mutation. The driving hypothesis in this proposal is that environmental exposure and/or aging may be required for determining the pathological phenotype in LRRK2-related disorders. To test this hypothesis, we will administer paraquat or diethyldithiocarbamate, alone and in combination, to two lines of human LRRK2 transgenic mice (LRRK2 overexpressors and G2019S mutant expressors) and wildtype littermates. The effect of toxic agents and/or aging on nigrostriatal vulnerability in LRRK2 transgenic mice will be examined in Aim 1, by evaluating locomotor activity, nigral dopaminergic cell number, striatal dopamine levels and glial activation. In Aim 2, we will assess the toxic protein species that likely contribute to degenerative events following pesticide exposure (i.e. tau and 1-syn), in both transgenic and wildtype mice. The third aim will evaluate the mechanisms of degeneration underlying LRRK2-related parkinsonism and whether distinct pathways are activated as a consequence of aging and toxicant exposure. This proposal assumes a multi-factorial etiology of parkinsonism and provides a unique opportunity to methodically evaluate the impact of each of these factors in novel transgenic models of PD. PUBLIC HEALTH RELEVANCE: Accumulating evidence indicates that environmental exposures can influence the development of Parkinson's disease (PD) and neurodegenerative disorders. Mutations in LRRK2 can cause a syndrome that mimics sporadic PD, but the same mutation, even within a single family, can result in various outcomes, presenting as typical PD in one member, but a different PD-related disorder with features such as cognitive impairment, in another. These findings suggest that exposure to environmental agents may affect the PD-related syndrome that develops in LRRK2-related disorders. In this proposal, we will test whether exposure to neurotoxicants (including those that have the potential for significant human exposures) can determine the behavioral and pathological features that develop in transgenic mice with altered human LRRK2 expression. Such studies may lead: (i) a better understanding of the mechanisms that contribute to the development of pathology in LRRK2 patients, but also (ii) provide insight into whether exposure to a specific toxicant can influence or even determine the development of a particular parkinsonian syndrome, including sporadic PD.